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Penetration is exponentially more effective the more you have of it, until you hit the exact number that is the opponent's defense at which point its effectiveness flatlines. Thus, the best jack-of-trades setup is to just stack tons of flat penetration as it provides the strongest early game that ends up being only a little weaker than the optimal lategame. This is partly why I promote early Brutalizer->Ghostblade builds so much -- excessive armor penetration forces the opponent to build defense and waste their gold, while you get extra stats which can often hit breakpoints (Urgot gets a 4th Q onto grenaded targets at 25% CDR, or Jarvan can Q to flag twice, etc.).

Stacking flat penetration isn't the end-all optimal build for everyone, but its cheap (IP-wise) and extremely effective on so many champions that it doesn't matter. Besides, you need high ratios for AD/AP level runes to be worth it, and too many champs have high bases with low ratios.

Item-wise, I also find flat penetration builds to be easiest to build for as well as they provide opportunity for generic sustain or defensive stats.

If your team is 2 AD, 1 AP, and you are a magic damage tank or the team is 2 AP, 1 AD, and you are a physical damage tank, build flat pen because it forces the enemy team to build both resists evenly or deal with a tank that has strong damage output, too, for relatively cheap. You basically want to force the enemy team to counter build you so that the real damage dealers on your team can do more.

If you get additional non-damage utility out of AP (such as a shield or heal) and/or have good ratios, AP can be better.

For blues and quints, I would almost always pick CDR over both, though.

Varies from champ to champ. Some with great ap ratios or who benefit from stacking AP in other ways (AP Yi) should go with AP/Level, while ones with high base values probably want to go heavier on MPen.

You're basically forced to go MPen on Reds though, since the AP options for those slots are NOT competitive numerically with the MPen ones at all.

The difference on AP chars between runes seems marginal ~ one auto attack difference from full combo at varying stages of the game.

That said, the difference seems like this: Mpen focus is stronger early game, with full AP catching up or overtaking later on (It seems that if your total burst is around Annie level, full ap stack catches up with mpen around 500 AP /w Void Staff). Full AP is basically utility and slightly more late game damage if you veer off to having lower bases and/or higher ratios than Annie.

The take away message imo, whatever offensive rune page you get will benefit you noticably. Your rule of thumb choice is between early game damage (use Mpen) and utility (i.e. AP heals/shields).

I think basically MPen runes will help you early more, probably pre level 12 or so. AP/level will be more efficient afterwards. So you can't really define a "better mix" of the two because a mix will just weight your strength more towards either early or late game power. It all depends on when you want to shine.